RELIEPH for Interstitial Cystitis

RELIEP 治疗间质性膀胱炎

• 批准号: 10133063
• 负责人: YAN XU
• 金额: $ 38.52万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133063
• 关键词: Absence of pain sensation; Acidosis; Address; Affect; Agonist; Amines; Analgesics; Antidepressive Agents; Basic Science; Behavioral; Binding Sites; Bladder; Bladder Control; Bladder Tissue; Cannabinoids; Caring; Cell Culture Techniques; Cell Line; Chemicals; Chlorides; Clinical; Clinical Research; Clinical Treatment; Cocaine; Cyclophosphamide; Data; Death Rate; Dependence; Development; Dose; Drug Addiction; Drug Prescriptions; Drug Tolerance; Drug abuse; Economics; Engineering; Etiology; Female; Fiber; Food; Frequencies; Future; Gene Delivery; Genes; Goals; Heroin; Human; Hyperactivity; Implant; Inflammation; Inflammatory; Injections; Institutes; Interstitial Cystitis; Intrathecal Injections; Intravesical Instillation; Legal patent; Ligand Binding; Ligands; Liposomes; Measurement; Measures; Medical; Medicine; Mental Health; Modeling; Nerve; Nerve Tissue; Neurons; Neurotransmitters; Nociception; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Nonpharmacologic Therapy; Opiate Addiction; Opioid; Outcome Measure; Overdose; Pain; Pain management; Patients; Peripheral; Peripheral Nerves; Pharmaceutical Preparations; Physiological; Polyamines; Prevalence; Process; Propylamines; Rattus; Recombinant adeno-associated virus (rAAV); Reporting; Research; Risk; Specificity; Stretching; Structure; Technology; Testing; Therapeutic Effect; Time; Treatment Efficacy; United States National Institutes of Health; Urination; Urine; Urothelial Cell; Urothelium; Woman; Xenopus oocyte; afferent nerve; base; bladder pain; chemical genetics; chronic pain management; chronic painful condition; design; designer receptors exclusively activated by designer drugs; effective therapy; food consumption; gene therapy; genetic technology; improved; improved outcome; in vivo; inflammatory pain; innovation; intravesical; male; men; nanoparticle; non-Native; opioid overdose; optogenetics; prescription drug abuse; prescription opioid; pressure; programs; public health relevance; receptor; receptor expression; response; sex; side effect; social; trend

About 7.9 million women and 4.6 million men in the US suffer from interstitial cystitis/bladder pain syndrome (IC/BPS). For many patients, the currently available treatments are inadequate and prone to adverse side effects, including potential dependence and abuse of prescription painkillers. An innovative nonpharmacological approach is proposed here to treat the debilitating condition of IC/BPS using a newly developed chemical genetics technology called RELIEPH (Receptor Engineering to Lessen Inflammation-Evoked Pain and Hyperactivity). The technology, which is based on the same principles as optogenetics and DREADD, will install engineered chloride (Cl–) channels into urothelial cells and peripheral nociceptors to control bladder hyperactivity and to alleviate pain in IC/BPS. The central hypothesis is that the expression of non-native Cl– channels in the neuron-like urothelial cells and in peripheral nerves can dynamically re-set the hypersensitization of the peripheral afferents without affecting the process of normal nociception. Two different types of “chemical genetic” designs will be tested in a rat model of IC/BPS. The first type acts passively by sensing inflammatory conditions such as acidosis in urothelial cells and peri-nerve tissues. Since etiology of IC/BPS is still unknown and inflammation is not always present, the second type is designed to selectively respond to small natural chemicals (including metabolites of certain food) that would otherwise have little or no analgesic action without the engineered Cl– channels. Promising preliminary data have demonstrated the efficacy of one of engineered channels in treating inflammatory pain and in restoring three outcome measures (intercontraction intervals, peak micturition pressure, and micturition pressure threshold) in a rat model of IC/BPS. The specific aims for the proposed new studies are: (1) design and optimize ligand-gated Cl– channels to be activated or modulated by primary and secondary amines found in common food; (2) quantify the physiological effects of the engineered Cl– channels in urothelial cell cultures by measuring ATP release and intracellular Ca2+; (3) devise and optimize effective gene delivery strategies by bladder instillation and peri-nerve injection using rAAV, liposomes, and functionalized nanoparticles, and quantify the engineered receptor expression and localization in urothelial cells and innervating afferents; and (4) evaluate the in vivo treatment efficacies and gene dose dependence to devise strategies to improve outcomes. The innovative idea and bold approaches proposed here will lead to the development of fundamentally new IC/BPS therapy that will greatly and effectively improve chronic pain management and reduce the risk of prescription drug abuse.

美国约有790万女性和460万男性患有间质性膀胱炎/膀胱疼痛 综合征（IC/BPS）。对于许多患者来说，目前可用的治疗是不充分的，并且容易发生并发症。 不良副作用，包括潜在的依赖和滥用处方止痛药。一个 本文提出了一种创新的非药物方法来治疗 IC/BPS使用新开发的化学遗传学技术，称为RELIEPH（受体 减轻炎症引起的疼痛和多动）。这项技术是基于 基于与光遗传学和DREADD相同的原理， 进入尿路上皮细胞和外周伤害感受器，以控制膀胱过度活动和减轻疼痛， IC/BPS。中心假设是非天然Cl-通道在神经元样细胞中的表达， 尿路上皮细胞和周围神经中的细胞可以动态地重置周围神经的超敏反应。 不影响正常的伤害感受过程。两种不同类型的“化学遗传” 将在IC/BPS大鼠模型中测试设计。第一种是被动地感知炎症 例如尿路上皮细胞和周围神经组织中的酸中毒的病症。由于IC/BPS的病因学仍然是 未知和炎症并不总是存在，第二种类型旨在选择性地响应于 小的天然化学物质（包括某些食物的代谢物），否则将很少或 没有工程Cl-通道就没有镇痛作用。初步数据显示， 证明了一种工程通道在治疗炎性疼痛和恢复 三个结果测量（收缩间期、排尿压力峰值和排尿压力 阈值）。新研究的具体目标是：（1）设计 并优化配体门控的Cl-通道以被伯胺和仲胺激活或调节 在普通食物中发现;（2）量化尿路上皮细胞中工程Cl-通道的生理作用 通过测定ATP释放量和细胞内Ca ~（2+）的变化来检测细胞培养物中ATP的释放量;（3）设计并优化有效基因 通过膀胱滴注和使用rAAV、脂质体和 功能化的纳米颗粒，并量化工程受体的表达和定位， 尿路上皮细胞和支配传入神经;和（4）评估体内治疗功效和基因 剂量依赖性，以制定改善结果的策略。 这里提出的创新思想和大胆方法将从根本上促进 新的IC/BPS疗法，将大大有效地改善慢性疼痛管理，并减少 滥用处方药的风险。